Current antibody-drug conjugates (ADC) have made advances in engineering the antibody, linker, conjugation site, small-molecule payload, and drug-to-antibody ratio (DAR). However, the relationship between heterogeneous intratumoral distribution and efficacy of ADCs is poorly understood. Here, we compared trastuzumab and ado-trastuzumab emtansine (T-DM1) to study the impact of ADC tumor distribution on efficacy. In a mouse xenograft model insensitive to trastuzumab, coadministration of trastuzumab with a fixed dose of T-DM1 at 3:1 and 8:1 ratios dramatically improved ADC tumor penetration and resulted in twice the improvement in median survival compared with T-DM1 alone. In this setting, the effective DAR was lowered, decreasing the amount of payload delivered to each targeted cell but increasing the number of cells that received payload. This result is counterintuitive because trastuzumab acts as an antagonist and has no single-agent efficacy, yet improves the effectiveness of T-DM1 Novel dual-channel fluorescence ratios quantified single-cell ADC uptake and metabolism and confirmed that the cellular dose of T-DM1 alone exceeded the minimum required for efficacy in this model. In addition, this technique characterized cellular pharmacokinetics with heterogeneous delivery after 1 day, degradation and payload release by 2 days, and cell killing and tumor shrinkage 2 to 3 days later. This work demonstrates that the intratumoral distribution of ADC, independent of payload dose or plasma clearance, plays a major role in ADC efficacy. This study shows how lowering the drug-to-antibody ratio during treatment can improve the intratumoral distribution of a antibody-drug conjugate, with implications for improving the efficacy of this class of cancer drugs. .

DM1 localizes perivascularly, as seen in multiple mouse models (4), due to its large size and high affinity to HER2 receptors.We and others have demonstrated that some ADC regimens can improve ADC distribution, efficacy, and tolerability. As previously established in our lab, the co-administration of T-DM1 with its unconjugated antibody, trastuzumab, improves drug penetration and efficacy (5). Other work from Hinrichs et al. and Jumbe et al. show that fractionating a single dose into 3 weekly doses can lead to similar efficacy, but better tolerability (6, 7). Despite these findings, the design principles underlying the best choice of regimen and drug combinations are not well-understood. For example, it is not clear if/when a 'carrier dose' will increase drug penetration and improve efficacy. The impact of HER2 expression level and payload potency on the increase or reduction in efficacy from a carrier dose are also not well defined. Finally, the interplay of dose fractionation with carrier doses on overall efficacy is currently unknown.Testing all combinations of receptor expression, payload potencies, carrier doses, dose fractionation regimes, etc. in vivo would be a daunting and expensive process. For this

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RESUMO Objetivo A pneumonia pneumocócica é uma causa significativa de morbimortalidade entre adultos. Desta maneira, o objetivo principal deste estudo foi avaliar a mortalidade intra-hospitalar e os custos relacionados à doença adquirida em adultos. Métodos Este estudo transversal utilizou prontuários de pacientes adultos com pneumonia pneumocócica internados em um hospital universitário no Brasil, de outubro de 2009 a abril de 2017. Todos os pacientes com idade ≥ 18 anos e diagnosticados com pneumonia pneumocócica foram incluídos. Dados como os fatores de risco, a internação em unidade de terapia intensiva, o tempo de internação, a mortalidade hospitalar e os custos diretos e indiretos foram analisados. Resultados No total, 186 pacientes foram selecionados. A taxa média de mortalidade intra-hospitalar foi de 18% para adultos com idade < 65 anos e 23% para os idosos (≥ 65 anos). A pneumonia pneumocócica bacterêmica acometeu 20% dos pacientes em ambos os grupos, principalmente por doença respiratória crônica (OR ajustada: 3,07; IC95%: 1,23‐7,65; p < 0,01). Após levantamento das internações ocorridas no período de sete anos de tratamento, verificou-se que os custos diretos e indiretos totais anuais foram de US$ 28.188 para adultos < 65 anos (US$ 1.746 per capita) e US$ 16.350 para os idosos (US$ 2.119 per capita). Conclusão A pneumonia pneumocócica continua sendo uma importante causa de morbimortalidade entre adultos, afetando significativamente os custos diretos e indiretos. Esses resultados sugerem a necessidade de estratégias de prevenção para todos os adultos, especialmente para pacientes com doenças respiratórias crônicas.

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